Transcriptional control by metal ions provides a useful paradigm to study eukaryotic gene regulation. When yeast cells are exposed to Cu, they repress transcription of the gene for cell surface reductase and activate transcription of the gene for metallothionein. Reductase catalyzes the conversion of Cu(II) to Cu(I), a new reaction discovered in this lab, whereas metallothionein chelates Cu and is involved in detoxification. The major cell surface reductase is encoded by FRE1, which was previously identified as an Fe reductase, while an alternative form is revealed in upc3l mutant strains. The major regulator of metallothionein gene transcription is ACEI, which contains a novel "copper fist" structure based on a polynuclear Cu(I)-S cluster. A second regulatory pathway is controlled by a heat shock transcription factor. Three proteins that regulate metallothionein gene transcription in mammals have been identified and are being characterized at the molecular level.